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      A proteomic approach to understanding the pathogenesis of idiopathic macular hole formation

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          Abstract

          Idiopathic macular holes (IMH) are full-thickness defects of retinal tissue that cause severe vision loss due to disruption of the anatomic fovea. Abnormal vitreous traction is involved in the formation of macular holes. Both glial cells and hyalocytes contribute to epiretinal membrane formation in IMH. In order to gain further insight into the pathophysiology of IMH, we conducted a discovery phase investigation of the vitreous proteome in four patients with macular holes and six controls using one-dimensional gel fractionation and liquid chromatography–tandem mass spectrometry analyses on an Orbitrap Elite mass spectrometer. Of a total of 5912 vitreous proteins, 32 proteins had increased and 39 proteins had decreased expression in IMH compared with controls, using a false discovery rate approach with p value < 0.001 and q value < 0.05. IMH was associated with increased expression of proteins in the complement pathway, α-2-macroglobulin, a major inducer of Müller glial cell migration, fibrinogen, and extracellular matrix proteins, and decreased expression of proteins involved in protein folding and actin filament binding. A proteomic approach revealed proteins and biological pathways that may be involved in the pathogenesis of IMH and could be targeted for future studies.

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          Most cited references27

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          Complement in immune and inflammatory disorders: pathophysiological mechanisms.

          Although acute or chronic inflammation is a common component of many clinical disorders, the underlying processes can be highly distinct. In recent years, the complement system has been associated with a growing number of immunological and inflammatory conditions that include degenerative diseases, cancer, and transplant rejection. It becomes evident that excessive activation or insufficient control of complement activation on host cells can cause an immune imbalance that may fuel a vicious cycle between complement, inflammatory cells, and tissue damage that exacerbates clinical complications. Although the exact involvement of complement needs to be carefully investigated for each disease, therapeutic modulation of complement activity emerges as an attractive target for upstream inhibition of inflammatory processes. This review provides an update about the functional and collaborative capabilities of complement, highlights major disease areas with known complement contribution, and indicates the potential for complement as a focal point in immunomodulatory strategies for treating inflammatory diseases.
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            α-2-Macroglobulin: a physiological guardian.

            Alpha macroglobulins are large glycoproteins which are present in the body fluids of both invertebrates and vertebrates. Alpha-2-macroglobulin (α2 M), a key member of alpha macroglobulin superfamily, is a high-molecular weight homotetrameric glycoprotein. α2 M has many diversified and complex functions, but it is primarily known by its ability to inhibit a broad spectrum of proteases without the direct blockage of the protease active site. α2 M is also known to be involved in the regulation, transport, and a host of other functions. For example, apart from inhibiting proteinases, it regulates binding of transferrin to its surface receptor, binds defensin and myelin basic protein, etc., binds several important cytokines, including basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), interleukin-1β (IL-1β), and interleukin-6 (IL-6), and modify their biological activity. α2 M also binds a number of hormones and regulates their activity. α2 M is said to protect the body against various infections, and hence, can be used as a biomarker for the diagnosis and prognosis of a number of diseases. However, this multipurpose antiproteinse is not "fail safe" and could be damaged by reactive species generated endogenously or exogenously, leading to various pathophysiological conditions. Copyright © 2012 Wiley Periodicals, Inc.
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              Anomalous posterior vitreous detachment: a unifying concept in vitreo-retinal disease.

              J. Sebag (2004)
              Posterior vitreous detachment (PVD) is the consequence of changes in the macromolecular structure of gel vitreous that result in liquefaction, concurrent with alterations in the extracellular matrix at the vitro-retinal interface that allow the posterior vitreous cortex to detach from the internal limiting lamina of the retina. Gel liquefaction that exceeds the degree of vitro-retinal dehiscence results in anomalous PVD (APVD). APVD varies in its clinical manifestations depending upon where in the fundus vitreo-retinal adhesion is strongest. At the periphery, APVD results in retinal tears and detachments. In the macula, APVD causes vitreo-macular traction syndrome, results in vitreoeschisis with macular pucker or macular holes, or contributes to some cases of diabetic macular edema. At the optic disc and retina, APVD causes vitreo-papillary traction and promotes retinal and optic disc neovascularization. Unifying the spectrum of vitreo-retinal diseases into the conceptual frame-work of APVD underscores that to more effectively treat, and ultimately prevent, these disorders it is necessary to replicate the two components of an innocuous PVD, i.e., gel liquefaction and vitreo-retinal dehiscence. Pharmacologic vitreolysis is designed to mitigate against APVD by chemically breaking down vitreous macromolecules and weakening vitro-retinal adhesion to safely detach the posterior vitreous cortex. This would not only facilitate surgery, but if performed early in the natural history of disease, it should prevent progressive disease.
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                Author and article information

                Contributors
                (410) 955-2571 , pzhang7@jhmi.edu
                zhumi@grc.nia.nih.gov
                zymyoyo@hotmail.com
                jiang.qian@jhmi.edu
                craig.dufresne@thermofisher.com
                rturner6@umd.edu
                rdsemba@jhmi.edu
                ssolomon1@jhmi.edu
                Journal
                Clin Proteomics
                Clin Proteomics
                Clinical Proteomics
                BioMed Central (London )
                1542-6416
                1559-0275
                15 November 2017
                15 November 2017
                2017
                : 14
                : 37
                Affiliations
                [1 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Wilmer Eye Institute, , Johns Hopkins University School of Medicine, ; Baltimore, MD USA
                [2 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, National Institute on Aging, , National Institutes of Health, ; Baltimore, MD USA
                [3 ]ISNI 0000 0001 2187 0556, GRID grid.418190.5, Thermo Fisher Scientific, ; West Palm Beach, FL USA
                Author information
                http://orcid.org/0000-0001-9248-5006
                Article
                9172
                10.1186/s12014-017-9172-y
                5688700
                29176938
                59b12603-120e-4d87-aabc-587f92b0280f
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 27 June 2017
                : 7 November 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: EY024596
                Award ID: AG027012
                Award Recipient :
                Funded by: Wilmer Eye Institute Pooled Professors Research Fund
                Funded by: the Edward N. & Della L. Thome Memorial Foundation
                Funded by: Research to Prevent Blindness (US)
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Molecular medicine
                eye,idiopathic macular hole,proteomics,retina,vitreous
                Molecular medicine
                eye, idiopathic macular hole, proteomics, retina, vitreous

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